Natural products have been capturing the interest and imagination of isolation, synthetic, and medicinal chemists for a very long time due to their fascinating structures and biological activities. Man-designed molecules ("designer molecules") with predefined chemical and biological properties could enrich and complement this arsenal of substances, and sharpen the capability of chemistry to deliver biologically and therapeutically useful compounds.
Described herein are the design, synthesis, chemical and biological actions of novel designer molecules with DNA cleaving and antitumor properties; for some recent examples of designed DNA-cleaving molecules, see: (a) Nicolaou et al., J. Am. Chem. Soc., 110:4866, 7247 (1988); (b) Nicolaou et al., Angew. Chem. Int. Ed. Engl., 28:1272 (1989); (c) Povsic et al., J. Am. Chem. Soc., 111:3059 (1989); (d) Hertzberg et al., J. Am. Chem. Soc., 104:313 (1982); (e) Moser et al., Science, 238:645 (1987); (f) Corey et al., J. Am. Chem. Soc., 111:8523 (1989); (g) Pyle et al., J. Am. Chem. Soc., 111:4520 (1989); (h) Sigman, J. Am. Chem. Soc., 111:4941 (1989); (i) Ohno et al., J. Am. Chem. Soc., 112:0000 (1990); (j) Danishefsky, J. Org. Chem., 54:2781 (1989); and Nicolaou et al., Angew. Chem. Int. Ed. Engl., 103:1032 (1991).
In addition to the man-made DNA cleaving compounds, naturally occurring ene-diyne compounds have also been reported and studies. Included among the naturally occurring enediynes are calicheamicin and esperimicin that have substantially identical aglycon portions but different sugar portions [(a) Lee et al., J. Am. Chem. Soc., 109:3464, 3466 (1987); (b) Nicolaou et al., J. Am. Chem. Soc., 110:7247 (1988); (c) Hawley et al., Proc. Natl. Acad. Sci. USA, 86:1105 (1989); (d) Golik et al., J. Am. Chem Soc., 109:3461, 3462 (1987)] and neocarzinostation that also contains sugar-derivative side chains [(a) Edo et al., Tetrahedron Lett., 26:331 (1984); (b) Chin et al. Biochemistry, 27:8106 (1988); (c) Lee et al., Biochemistry, 28:1019 (1989)].